If you want to denature ovalbumin, just add a little heat. The resulting white glob looks nothing like the native protein, yet little has changed. No covalent bonds have been broken or formed-the protein is just folded differently. So what enables a one-dimensional polypeptide chain peeling off a ribosome to assume its correct three-dimensional form? It was once thought that the primary amino acid sequence contained all the information necessary for the protein to fold up right, and though this may be true for some small proteins, many larger proteins need help getting into shape.

Ulrich Hartl and Manajit Hayer-Hartl at the Max-Planck Institute for Biochemistry, Martinsried, Germany, review current knowledge on protein folding and chaperones, the physical trainers of the cell. Chaperones not only help nascent polypepetides fold, they also protect them from proteins with which they should not associate. In the densely packed cytoplasm of the average cell, it is easy to mix with the wrong crowd, and when this happens the result is often an insoluble aggregate that is impossible to break apart. Examples of such aggregates include neurofibrillary tangles, amyloid plaques, and Lewy bodies.

Hartl and Hartl describe how most chaperones work by binding to hydrophobic stretches in nascent proteins that would normally be buried within the interior of the native protein. Keeping these sticky sections away from other proteins is the key to preventing aggregation. Though unboiling ovalbumin is probably beyond the scope of most chaperones, some are capable of refolding misfolded proteins.

In the field of neurodegenerative diseases protein aggregation is a familiar theme. Recent evidence has pointed to the beneficial role of chaperones in preventing such aggregates. For example, chaperones of the heat shock family are capable of preventing dopaminergic neuron loss and cellular degeneration seen in fly models of Parkinson's disease (see earlier ARF news story), and Huntington's disease (Kazemi-Esfarjani 2000), respectively, while hsp40 improves motor function in a mouse model of human spinocerebellar ataxia (Cummings et al. 2001). The protein folding machinery may, therefore, be key to the control and regulation of neuronal protein aggregation.—Tom Fagan